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Mini-Review
Cite This: ACS Omega 2019, 4, 22261−22273
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Diversity-Oriented Approaches to Polycycles and Heterocycles via
Enyne Metathesis and Diels−Alder Reaction as Key Steps
Sambasivarao Kotha,*,† Arjun S. Chavan,‡,# and Deepti Goyal§,#
†
Department of
Department of
§
Department of
140406 Punjab
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‡
Chemistry, Indian Institute of Technology Bombay, Mumbai 400076, India
Chemistry, Thakur College of Science and Commerce Kandivali (E), Mumbai 400101, India
Chemistry, Faculty of Basic and Applied Sciences, Sri Guru Granth Sahib World University, Fatehgarh Sahib,
India
ABSTRACT: Enyne metathesis (EM) has extensively been
used to prepare diverse polycycles and heterocycles. EM in
combination with Diels−Alder (DA) reaction has been used
to prepare densely functionalized targets in a simple manner.
In this mini-review, we discuss the various diversity-oriented
approaches reported from our laboratory to prepare a variety
of organic frameworks by a synergistic combination of EM
and DA reactions. Some of the end products are useful
intermediates for the synthesis of complex organic targets.
■
INTRODUCTION
Enyne metathesis (EM)1 is a bond reorganization process
between alkynes and alkenes to produce conjugated 1,3-dienes
(Scheme 1). It involves the simultaneous bond cleavage and
Scheme 1. Intermolecular and Intramolecular Enyne
Metathesis
Figure 1. Precatalysts used for the metathesis.
containing a six-membered ring can be generated by utilizing
the EM−DA approach. The designed approach is diversityoriented, as a combinatorial library of target compounds could
be assembled by varying the diene and the dienophile
component in a DA reaction. The final six-membered ring
compounds are the core structure of various biologically relevant
drug-like molecules and structural analogues of bioactive natural
products.3 More specifically, cross-metathesis (CM) and RCEM
provide an easy access to generate various dienes containing
polar functional groups. The generation of such intricate dienes
is a difficult task by conventional methods.
In 1985, Katz and Sivavec first reported the intramolecular
RCEM with a tungsten carbene complex, where the diene 7 was
generated from the enyne 6 by treating with a catalytic amount
of tungsten carbene complex (Scheme 2).4a Later, in 1994, Mori
and Kinoshita reported the first example of intramolecular enyne
metathesis catalyzed by Grubbs’ catalyst, where the enyne
building block 8 was treated with a ruthenium catalyst to
generate the cyclic diene 9 (Scheme 3).4b
bond formation. This reaction is generally catalyzed by a
ruthenium catalyst, Grubbs’ first-generation precatalyst (G-I),
Grubbs’ second-generation precatalyst (G-II), and Hoveyda−
Grubbs’ precatalysts (HG-I and HG-II) etc. (Figure 1). The
intermolecular process is called a cross-enyne metathesis (CEM,
Scheme 1), whereas the intramolecular reactions are referred to
as ring-closing enyne metathesis (RCEM, Scheme 1). EM is a
very expedient tool to generate a 1,3-diene moiety, which is a
strategic component in the DA reaction to generate diverse
polycyclic compounds.2 A large number of compounds
© 2019 American Chemical Society
Received: September 16, 2019
Accepted: November 29, 2019
Published: December 16, 2019
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O’Donnell Schiff base 10 was subjected to a propargylation,
allylation, hydrolysis, and acetylation reaction sequence to
generate the enyne building block 11.5c Later, enyne 11 was
subjected to EM to generate the key inner−outer ring diene
building block 12, which on DA reaction with various
dienophiles and subsequent dehydrogenation with 2,3dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) delivered the
indanyl glycine derivatives 13a,b and 14−15. The present
strategy provides a “green route” to indanyl glycine derivatives as
both EM and DA are atom-economic reactions. Later, this
strategy has been used to generate various molecular frameworks.6
In 2011, Reddy’s group reported a first total synthesis of
bicyclic diterpene, isofregenedadiol 19, by utilizing a one-pot
reaction sequence involving RCEM, CM, DA reaction, and
aromatization (Scheme 5).7 Later in 2014, Reddy and coworkers used a similar strategy to report the first total synthesis
of a norsesquiterpene alkaloid, (R)-8-hydroxy-4,7,7-trimethyl7,8-dihydrocyclopenta[e]isoindole-1,3(2H,6H)-dione 23. The
synthetic strategy involves a RCEM, DA reaction, and
aromatization sequence to generate the desired indane skeleton
present in the natural product. The resulting indane-based
diester 21 was transformed into a target anticancer agent by
hydrolysis, conversion of diacid to imide 22, and subsequent
removal of the benzyl group to deliver the compound 23
(Scheme 6).8
Recently, Kaliappan and Sayyad have reported the synthesis of
a new class of sugar−oxasteroid−quinone hybrid molecules 26
via sequential EM−DA strategy (Scheme 7).9 By utilizing this
approach with various enyne-containing sugar molecules, they
have prepared a library of hybrid molecules with a steroid-like
backbone.
2. Tetrahydroisoquinoline-3-carboxylic Acid (Tic)
Derivatives. Later, the above strategy involving EM−DA
reactions has been extended for the synthesis of topographically
constrained Tic derivatives 29−30 (Tic, a constrained analogue
of Phenylalanine (Phe), Scheme 8).10a
Tic derivatives are conventionally prepared by Pictet−
Spengler or Bischler−Napieralski reactions, which start with
the preformed benzene derivatives. Moreover, these methods
Scheme 2. Intramolecular Enyne Metathesis by a Tungsten
Carbene Complex
Scheme 3. Intramolecular Enyne Metathesis by a Ruthenium
Carbene Complex
Here, we summarize our efforts to prepare various diene
building blocks via EM and their subsequent utilization in the
synthesis of highly functionalized and intricate carbocyclic and
heterocyclic frameworks. More specifically, the EM and DA
sequence has been used to prepare various modified amino acid
derivatives, polycycles, macroheterocycles, heterocycles, crownophanes, diphenylalkane derivatives, and spirocycles. Some of
these building blocks were further incorporated into small
peptides, thus generating a library of modified peptides. We have
grouped the EM−DA reaction strategies based on the class of
the final product, i.e., polycycles, heterocycles, amino acid
derivatives, crownophanes, spirocycles, etc. As and when
necessary, we have included others references also.
1. Indane-Based α-Amino Acid Derivatives and
Natural Products. The Buchrer−Burg method is generally
employed to generate indanyl glycine; however, this methodology is impractical for sensitive substrates due to the harsh
conditions employed during the hydrolysis of hydantions.
Therefore, a conceptually new approach by using EM and DA
reaction in synergistic combination was utilized to assemble
indanyl glycine derivatives (Scheme 4).5a,b In this regard,
Scheme 4. Indanyl Glycine Derivatives
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Scheme 5. Total Synthesis of Isofregenedadiol by EM−DA Strategy
the existing methods, as diverse substituents in the benzene ring
can be incorporated by the careful selection of reacting partners.
3. Modified Phenylalanine-Based α-Amino Acids and
Peptides. The strategy involving CEM and DA reaction as key
steps was further utilized for the synthesis of highly functionalized Phe derivatives (Scheme 10).10c,d The beauty of this
strategy is that Phe-based α-amino acid (AAA) derivatives are
assembled from building blocks having no Phe moiety. To this
end, the acetylenic building blocks 36 were prepared from the
Schiff base 10 or 35, and later it was reacted with allyl acetate, a
functionalized ethylene derivative to deliver the diene 37 as a
mixture of isomers (1:1). No attempts were made to separate
these isomers as the stereochemistry of the diene 37 is of no
consequence for the synthesis of final Phe derivatives. The DA
reaction of 37 with DMAD and subsequent oxidation of the DA
adducts delivered the highly functionalized Phe derivatives 38. It
is worthy to mention that the diene 37 could not be synthesized
from CEM of alkynes and the allyl building blocks containing an
AAA moiety.
In another instance, the Schiff base 10 was subjected to a Cpropargylation, hydrolysis, and protection sequence to generate
the alkyne building block 31. Later, CEM of the alkyne building
block 31 with ethylene as a cross-coupling partner gave the diene
39. Then, treatment of the diene 39 with various dienophiles
and subsequent aromatization of the DA adduct delivered a
highly functionalized Phe derivative 40 (Scheme 11).11 Further,
the alkylation of ethyl isocyanoacetate (EICA) with 2bromomethyl-1,3-butadiene 41 or sulfolene bromide 42 failed
to deliver the diene 39 (Scheme 11).10c−e In another report, the
analogue of diene was prepared by using N-acyliminium ion
chemistry.12a
A similar diene containing the AAA derivative 46 was
reported by Baldwin and co-workers using Denmark’s coupling
reaction (Scheme 12).12b
In another attempt, dicarba analogues of cystine derivatives
such as 51 were prepared by using a CEM and DA approach
(Scheme 13).11
Scheme 6. Total Synthesis of a Norsesquiterpene Alkaloid by
EM−DA Strategy
are not suitable for substrates containing electron-withdrawing
groups due to the involvement of electrophilic aromatic
substitution reaction. To realize the EM−DA strategy, the
required enyne building block 27 was prepared from Schiff base
ester 10 via C-allylation and hydrolysis reaction followed by the
N-protection and N-propargylation. Later, EM of building block
27 using the G−I catalyst gave the required inner−outer ring
diene building blocks 28. Finally, the DA reaction of the dienes
28 with dimethyl acetylenedicarboxylate (DMAD) and
quinone, followed by subsequent oxidation of the DA adducts,
generated the Tic derivatives 29 and 30, respectively, in good
yields. The present methodology quickly improves the diversity
and molecular complexity and provides access to intricate Tic
derivatives.
Further, the above methodology has been extended to the
synthesis of a highly substituted seven-membered analogue of
Tic 34 (Scheme 9).10b In this context, initially the amide
nitrogen in the compound 31 was N-alkylated with butenyl
bromide, and then the compound 32 was subjected to EM to
generate the diene 33, which on DA reaction with DMAD
followed by oxidation using DDQ delivered the desired
analogue of Tic 34. The present strategy is advantageous over
Scheme 7. Sugar−Oxasteroid−Quinone Hybrid Molecules via EM−DA Strategy
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Scheme 8. Constrained Tetrahydroisoquinoline-3-carboxylic Acid (Tic) Derivatives
Scheme 9. Seven-Membered Analogue of Tic Derivatives
Scheme 11. Highly Functionalized Phe Derivative
The benzophenone imine glycine ester 10 was reacted with
1,4-dibromo-2-butyne (48), followed by hydrolysis, and
acetylation gave the alkyne derivative 49 (two diastereomers
in 1:1 ratio; RR/SS, and RS/SR). The bis(amino acid) derivative
49 was subjected to CEM in the presence of ethylene and HG-II
catalyst to afford the desired diene 50. Finally, the DA reaction
of diene 50 with various dienophiles gave the conformationally
rigid dicarba analogues of cysteine 51.
Further, the above strategy was extended toward the
postassembly peptide modification.13a To realize the synthetic
strategy, the alkyne-based dipeptide 52 was synthesized from
diethyl acetamidomalonate (DEAM) (43). To the end, CEM of
alkyne 52 with ethylene as a cross-coupling partner delivered the
diene 53, which on treatment with DMAD followed by
aromatization with MnO2 generated the desired modified Phebased dipeptide 54 (Scheme 14). In addition, the same strategy
was extended to tripeptide-based alkyne building block 55, and
the DA reaction was also realized with 1,4-napthaquinone to
establish the diversity of this approach (Scheme 15).
4. Crownophane. Recently, we reported a diversityoriented approach to crownophanes by utilizing CEM and DA
reactions as key steps (Scheme 16).13b Initially, the diene 59 was
generated by CEM of alkyne precursor 58 in the presence of
Grubb’s catalyst under an ethylene atmosphere. Later, the DA
reaction of the diene 59 with DMAD followed by aromatization
of the cycloadduct with DDQ gave the crownophane 60. It is
worth noting that the present strategy involved the creation of
eight new C−C bonds and thereby accomplishing step economy
and atom economy. The above strategy was further employed to
assemble ortho- and meta-crownophanes.
Later, another derivative of crownophane 63 was assembled
by utilization of the above strategy (Scheme 17).13b In this
regard, the crownophane-based acetylenic derivative 61 was
subjected to CEM under an ethylene atmosphere to generate the
diene 62. Then, the DA reaction of diene 62 with DMAD
followed by aromatization of the cycloadduct gave the desired
crownophane 63. Similarly, this strategy was extended to orthoand meta-crownophanes.
5. Diphenylalkane Derivatives. In 2009, a useful strategy
has been realized to highly functionalized diphenylalkane
derivatives via atom-economical processes such as [2 + 2 + 2]
cyclotrimerization, CEM, and DA reaction as key steps (Scheme
18).13c
To this end, the alkyne building blocks 66 were prepared by
the [2 + 2 + 2] cyclotrimerization of dialkyne 64 and DMAD in
the presence of Wilkinson’s catalyst [Rh(PPh3)3Cl]. Later, the
CEM of the alkyne 66 in the presence of G-II catalyst under an
Scheme 10. Synthesis of Functionalized Phenylalanine (Phe) Derivatives
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Scheme 12. Generation of a Diene-Containing Amino Acid Moiety
Similarly, the phenylacetylene 69 was subjected to CEM with
1,5-hexadiene to generate the desired homoallyl diene
derivatives 72 along with the benzoannulated product 73
(Scheme 20).14 The DA reaction of dienes 72 with DMAD gave
the DA adduct, which on aromatization with DDQ generated
the biphenyl derivatives 74. Later, this strategy has been
extended toward the synthesis of amino acid derivatives 74a and
74b.16
6. Spirocycles. In 2007, we reported a unique example
involving sequential RCM and CEM.17 Three products (76−
78) were isolated when the enyne precursor 75 was treated with
G-I in the presence of ethylene (Scheme 21). On the contrary,
two products 79 and 80 were isolated when the enyne precursor
75 was treated with G-II in dichloromethane (DCM) at room
temperature. The compound 79 has been derived by EM at one
alkyne end and compound 80, due to EM at both alkyne ends.
When the compound 75 was treated with the G-II catalyst under
ethylene-free reaction conditions, no metathesis product was
observed, but the G-I catalyst with in situ generated ethylene
reacted with alkyne moieties. In this strategy, chemoselectivity
was observed with G-I and G-II catalysts under an ethylene
atmosphere. The reactions of enyne precursor 75 under G-I, GII, and HG-II catalyst conditions failed to give the bis-spirocyclic
diene 81 (Scheme 22).
Recently, a simple diversity-oriented methodology for the
synthesis of indane-based spirocycles has been developed via
EM and DA reaction, as key steps (Scheme 23).18a The enyne
building block 82 was assembled by monopropargylation
followed by allylation of the indane-1,3-dione. Later, the
enyne building block 82 was subjected to ring-closing enyne
metathesis in the presence of G-II catalyst. A catalytic amount of
titanium isopropoxide and ethylene atmosphere was found to
increase the yield of 83. The diene 83 was treated with various
dienophiles to produce the corresponding DA adducts. Then,
the DA adducts were subjected to oxidation with MnO2 to
deliver the corresponding aromatized spirocycles 84. This work
has been highlighted in Synfacts.18b
Scheme 13. Dicarba Analogues of Cystine Derivatives
ethylene atmosphere delivered the dienes 67, which on DA
reaction with DMAD followed by aromatization gave the highly
functionalized diphenylalkane derivatives 68. The beauty of the
present strategy is that we accomplished desymmetrization in
highly symmetrical starting materials, i.e., α,ω-diynes.
In another event, we have demonstrated that CEM of
phenylacetylene derivatives with 1,5-hexadiene or ethylene
followed by the DA reaction and aromatization sequence
delivered biaryl derivatives (Scheme 19 and Scheme 20).14 To
realize the synthetic design, phenyl acetylenes 69 were subjected
to CEM in the presence of G-II catalyst under an ethylene
atmosphere to generate the corresponding dienes 70. Later, the
DA reaction of the dienes 70 with DMAD followed by
aromatization with DDQ gave biphenyl derivatives 71. The
halogen substituent present in the biaryl derivative is a useful
handle to the Suzuki−Miyaura (SM) cross-coupling reaction15
to generate the terphenyl derivative. The present strategy can
provide an easy access to a library of biaryl (or terphenyl)
building blocks via Suzuki coupling by using a variety of
commercially available boronic acids.
Scheme 14. Phe-Based Dipeptide
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Scheme 15. Phe-Based Tripeptide
Scheme 16. Paracrownophanes via EM−DA Strategy
Scheme 17. Crownophane via EM−DA Strategy
Scheme 18. Functionalized Diphenylalkane Derivatives
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Scheme 19. Biaryl Derivatives via EM−DA Strategy
Scheme 20. Homoallyl Derivatives via EM−DA Strategy
Scheme 21. Sequential RCM and CEM
Scheme 22. Attempt to Bis-spirocyclic Diene
Scheme 23. Indane-Based Spirocyclesa
a
Dienophile: 1,4-benzoquinone (57%), 1,4-naphthoquinone (49%), 1,4-anthraquinone (55%), DMAD (76%), N-phenylmaleimide (65%).
The above strategy was expanded to generate diverse
spirocycles 88 by varying the active methylene compound
(AMC), such as indane-1-one, 1-tetralone, 6-methoxy-1tetralone, and diethyl malonate (Scheme 24).18c A variety of
enyne building blocks 86 were prepared by the sequential
allylation followed by propargylation of the corresponding active
methylene compound 85. Later, the enyne building blocks were
treated with G-II catalyst under an ethylene atmosphere in the
presence of titanium tetraisopropoxide to generate dienes 87.
These dienes were further utilized to generate a library of
angularly fused spirocyclic compounds 88 by reacting with a
variety of dienophiles such as DMAD, tetracyanoethylene, 1,422267
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Scheme 24. Diverse Spirocycles
rearrangement (CR) and subsequent O-propargylation of 97.
Later, these enynes 98 were successfully transformed into the
required diene 99 by G-II catalyst. These dienes on DA reaction
with various dienophiles generated the polycyclic frameworks
such as 100 (Scheme 27).21
In 2007, tandem cross-enyne ring-closing metathesis (CERCM) was explored to generate densely functionalized
macroheterocycles (Scheme 28).22a To realize the synthetic
sequence, N-tosyl glycine 101 was subjected to esterification
with propargyl bromide to yield the ester 102. The Opropargylated compound 102 was then allylated using allyl
bromide to deliver the enyne precursor 103. Later, enyne 103
was subjected to CE-RCM with 1,5-hexadiene to deliver the
desired 12-membered macrocyclic compound 104 along with an
open-chain product 105. Further, the strategy was extended to
generate macrocyclic systems of 13−16-membered ring size
(107) by varying the size of alkenylation partner.
The above methodology was utilized to assemble C-α,αfunctionalized macrocyclic AAA derivative 111 (Scheme 29).22b
In this regard, a suitable enyne precursor 110 was synthesized
from DEAM (43) in three steps. To begin with, DEAM was
partially hydrolyzed and subjected to O-propargylation to
deliver the ester 109, which was then subjected to C-allylation
with allyl bromide to generate the required enyne precursor 110.
Later, treatment of the enyne 110 with 1,5-hexadiene in the
presence of a Grubb’s catalyst delivered the desired 12membered macrocyclic AAA derivative 111 in 40% yield,
along with the open-chain compound 112 in 54% yield.
Systematic catalyst screening resulted in the selective formation
of the desired macrocyclic AAA derivative, and with the HG-I
catalyst, the cyclic AAA derivative 111 was obtained in 86%
yield.
In 2015, Fustero’s group has reported a tandem CEM and
intramolecular DA reaction methodology for the generation of
linear bicyclic ketone, lactone, and lactam scaffolds in a simple
manner with good diastereoselectivity (Scheme 30).23 In this
regard, various conjugated ketones, esters, and amides bearing
an alkene moiety 113 were reacted with different aromatic
alkynes 114 in the presence of HG-II catalyst to obtain the
bicyclic ketone, lactones, and lactams 115. The resulting bicyclic
benzoquinone, 1,4-naphthoquinone, 1,4-anthraquinone, 4phenyl-1,2,4-triazoline-3,5-dione, and N-phenylmaleimide.
7. Heterocycles. The strategy involving the EM−DA
reaction was utilized by Dixneuf and co-workers for the
synthesis of cyclic siloxanes 92 (Scheme 25).19 They have
Scheme 25. Synthesis of Cyclic Siloxanes via EM−DA
Reaction
reported the intramolecular metathesis of enynes 89 containing
the Si−O linkage with ruthenium-based three-component
catalytic systems to generate the dienes 90. The resulting sixmembered siloxane dienes 90 were utilized in DA reaction
followed by aromatization of the resulting DA adduct 91,
generating the aromatic compound 92 which is an important
precursor for sol−gel materials and fine chemicals.
Similarly, Majumdar and co-workers have applied the EM−
DA strategy to generate tricyclic oxepin-annulated pyrone
derivatives 95 (Scheme 26).20 In this regard, the pyrone-based
enyne derivatives 93 were subjected to RCEM to produce
oxepin-annulated pyrone-based diene derivatives 94. These
dienes 94 on DA reaction with dimethyl fumarate gave tricyclic
oxepin-annulated pyrone derivatives 95 stereoselectively.
Kotha’s group has successfully utilized the EM and DA
reaction strategy for the generation of heterocycles. In this
regard, the required enyne building blocks 98 were prepared
from the β-naphthols 96 by O-allylation followed by Claisen
Scheme 26. Synthesis of Tricyclic Oxepin-Annulated Pyrone Derivatives
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Scheme 27. Polycyclic Frameworks via EM−DA Strategy
Scheme 28. Functionalized Macroheterocycles
Scheme 29. Macrocyclic AAA Derivative
which on treatment with various dienophiles generated the
Scheme 30. Bicyclic Scaffolds via EM−DA Strategy
cycloadducts such as 119 (Scheme 31).24a
Scheme 31. Oxacycles via EM−DA Strategy
heterocycles 115 were formed via tandem CEM and an
intramolecular DA reaction sequence.
In 2014, Kotha’s group has developed a diversity-oriented
approach to fused oxacycles 119 by using the enyne ringrearrangement metathesis (ERRM) and DA reaction as key
steps starting with a suitable propargylated derivative 117. The
propargylated derivative 117 was derived from 1β-dicyclopentadienol 116. Then, ERRM of 117 in the presence of ethylene
and G-I catalyst delivered the rearranged tricyclic diene 118,
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Scheme 32. Enyne Ring-Rearrangement Metathesis (ERRM)
derivatives (Scheme 34 and Scheme 35).24c In this aspect, the
diol 129 was prepared from dione 120 by treating it with
Similarly, our group has developed a simple synthetic strategy
to construct the oxa-bowls containing dienes by utilizing ERRM
as a key step (Scheme 32).24b In this regard, the required
norbornene derivatives 121 were prepared by DA reaction of
cyclopentadiene and quinone followed by the reduction of DA
adduct 120. Then the diol 121 was subjected to Opropargylation using propargyl bromide to generate the
dipropargylated norbornenes 122, which were subsequently
converted to dienes 123 by ERRM. These dienes 123 can be
further utilized for creating the polycycles by DA strategy, but
these dienes are found to be unstable under normal DA reaction
conditions.
The ERRM strategy was extended toward the synthesis of oxabowl-based polycyclic compound 128. In this regard, tricyclic
enone 124 was reduced to tricyclic diol 125, which was Opropargylated using propargyl bromide to generate an enyne
building block 126. The ERRM of enyne building block 126 in
the presence of a G-I catalyst gave the oxa-bowls containing
diene 127. Later, the DA reaction of the diene 127 with Nphenylmaleimide generated the polycyclic compound 128
(Scheme 33). By varying the dienophile moiety, one can
prepare a library of polycyclic compounds.
Scheme 35. Synthesis of Structurally Intricate Polycyclic
Compound 132
allylmagnesium bromide. Then, the treatment of diol 129 with
propargyl bromide generated the mono-O-propargyl derivative
130, which was subjected to the RCEM−RRM sequence in the
presence of HG-II catalyst under an ethylene atmosphere to
deliver the tetracyclic diene 131. When the compound 131a was
reacted with tetracyanoethylene (TCE) in refluxing toluene, the
dehydrated product 132 was isolated, which is derived from the
DA adduct (Scheme 35).
In 2017, a new synthetic strategy to fused nitrogen containing
heterocycle 136 was demonstrated by using the ERRM−DA
protocol (Scheme 36).24d In this context, when the N-propargyl
derivative 133 was treated with a G-I catalyst in the presence of
ethylene, a mixture of two products 134 and 135 was formed.
The compound 134 was derived by ERRM and compound 135
by ring-opening reaction. The ring-opened product 135
underwent EM in the presence of ethylene and a G-I catalyst
to deliver the desired diene 134 in good yield. Later, the DA
reaction of the diene 134 with tetracyanoethylene (TCE) gave
the cycloadduct 136. Interestingly, the pentacyclic compound
136 possesses the tricyclic core of the alkaloid, epimeloscine.
8. Miscellaneous. We have also reported the generation of
dienes starting with protected, but-2-yne-1,4-diol derivatives
137 by CEM under ethylene atmosphere (Scheme 37).25 The
acyl-protected diene 138a is a suitable starting material to
assemble benzoannulated compound 139, which can be further
utilized for the synthesis of polycyclic compounds through a
regioselective DA reaction of the benzosultine-sulfone building
Scheme 33. Oxa-Bowl-Based Polycycle
Along similar lines, a structurally intricate polycyclic
compound 132 has been synthesized through rutheniumcatalyzed ring-rearrangement metathesis (RRM) of norbornene
Scheme 34. Polycyclic Diene through RCEM−RRM
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Scheme 36. ERRM−DA Protocol
Scheme 37. Benzoannulation via EM−DA Reaction
block 140. The DA reaction of tosyl-protected diene 138b with
various dienophiles under different conditions was unsuccessful.
However, the DA reaction of acetyl derivative 138a with DMAD
gave the expected DA adduct. Later, the DA adduct was
subjected to aromatization using DDQ in benzene or MnO2 in
dioxane under reflux conditions to generate the desired
benzoannulated product 139.
■
Biographies
SUMMARY AND OUTLOOK
In this account, we have summarized various synthetic strategies
to prepare diverse diene building blocks via EM and their use in
assembling a variety of polycyclic compounds. The synergetic
approach of the EM and DA sequence has been utilized to
prepare various unnatural amino acid derivatives, modified
peptides, polycycles, heterocycles, and spirocyclic compounds.
This synergetic approach can be employed to prepare various
biologically important molecules or chemical intermediates,
which may inspire the synthesis of pharmaceutically important
compounds.
■
Sambasivarao Kotha graduated with an M.Sc. degree in Chemistry from
University of Hyderabad and then obtained a Ph.D. in Organic
Chemistry from University of Hyderabad in 1985. He continued his
research at the University of Hyderabad as a postdoctoral fellow for one
and half years. Later, he moved to UMIST Manchester, UK, and the
University of Wisconsin, USA, as a research associate. Subsequently, he
was appointed as a visiting scientist at Cornell University and as a
AUTHOR INFORMATION
research chemist at Hoechst Celanese Texas prior to joining IIT
Corresponding Author
*E-mail: srk@chem.iitb.ac.in. Phone: +91 22 25767160. Fax:
+91 22 25767152.
Bombay in 1994 as an Assistant Professor. In 2001, he was promoted to
ORCID
and was elected fellow of various academies (FNASc, FASc, FRSC, and
Sambasivarao Kotha: 0000-0002-7173-0233
FNA). He was also associated with the editorial advisory board of
Author Contributions
several journals. His research interests include: Organic synthesis, green
Professor. He has published 285 publications in peer-reviewed journals
#
chemistry, unusual amino acids, peptide modification, cross-coupling
A.S.C. and D.G. equally contributed to this work.
Notes
reactions, and metathesis. Currently, he occupies the Pramod
The authors declare no competing financial interest.
Chaudhari Chair Professor in Green Chemistry.
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DOI: 10.1021/acsomega.9b03020
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ACS Omega
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Mini-Review
REFERENCES
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Arjun S. Chavan graduated with an M.Sc. degree in Chemistry from
Shivaji University, Kolhapur, and then obtained a Ph.D. in Organic
Chemistry from IIT Bombay, India, in 2012 under the supervision of
Prof. S. Kotha. Afterwards he joined National Chiao Tung University
Hsinchu, Taiwan, and worked with Prof. S. C. Chuang as a Postdoctoral
Fellow. Presently, he is Assistant Professor at Department of Chemistry,
Thakur College of Science and Commerce Kandivali (E) Mumbai,
India. His research interests include green chemistry, use of recyclable
catalysts in organic synthesis, nanomaterials, and nanocatalysis.
Deepti Goyal obtained her M.Sc. (Honours School) degree from
Panjab University, Chandigarh, in 2006 and a Ph.D. degree from Indian
Institute of Technology (IIT), Bombay, Mumbai, India, in 2012 under
the supervision of Prof. S. Kotha. She is presently working as an
Assistant Professor in the Department of Chemistry, Sri Guru Granth
Sahib World University, Fatehgarh Sahib, Punjab, India. The Science
and Engineering Research Board (SERB), Government of India,
awarded her a Young Scientists Research Grant in 2015. Her research
interests focus on the design, synthesis, and evaluation of new molecular
entities (small molecules, peptides, and peptidomimetics) as inhibitors
of amyloid aggregation.
■
ACKNOWLEDGMENTS
We thank CSIR, UGC, and DST, New Delhi, for the financial
support. S.K. thanks the Department of Science and Technology
(DST), New Delhi, for the award of a J. C. Bose fellowship (SR/
S2/JCB-33/2010), Praj Industries, Pune, for a Chair Professorship (Green Chemistry), and Council of Scientific and Industrial
Research (CSIR), New Delhi [02(0272)/16/EMR-II], for the
financial support. A.S.C. would like to thank Thakur College of
Science and Commerce Kandivali, Mumbai, for providing an
infrastructure. D.G. would like to thank Sri Guru Granth Sahib
World University, Fatehgarh Sahib, Punjab, for providing an
infrastructure.
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22273
DOI: 10.1021/acsomega.9b03020
ACS Omega 2019, 4, 22261−22273